Ebola virus (EV) causes hemorrhagic fever in humans and non-human primates. Among emerging infectious diseases, EV stands out for its impressive lethality. Acute mortality due to the Zaire strain of EV has been approximately 80% in human outbreaks. There is currently no therapy. [unreadable] The molecular pathogenesis of EVHF remains poorly understood. Recent studies have suggested that massive apoptosis of lymphocytes, along with dysregulated production of IFN-a, plays an important role in the pathogenesis of EVHF: [unreadable] (1) Survivors and fatalities have similar viral loads at the onset of illness. In fatalities, widespread lymphocyte apoptosis occurs prior to the development of an adequate adaptive (B and T cell mediated) immune response. In survivors, the adaptive immune response, arising in the absence of such pathological lymphocyte apoptosis, leads to viral clearance and disease resolution. Such large- scale lymphocyte apoptosis, associated with profound lymphopenia and destruction of lymphoid tissue, is recapitulated in macaque models of EVHF. The mechanism(s) underlying such apoptosis remains unclear. It is not due to direct viral infection; EV does not infect lymphocytes. [unreadable] (2) EVHF is associated with sustained high expression of IFN-a. In vitro infection of monocytes, cells that form a primary site of EV replication in vivo, also induces high levels of IFN-a secretion. In addition to driving the activation of NK cytolytic pathways (notable, given circumstantial evidence for granzyme B-mediated cytolytic pathways in EVHF-related lymphocyte apoptosis), IFN-a can directly induce lymphocyte apoptosis, through caspase-dependent and -independent mechanisms. [unreadable] The interrelated hypotheses underlying the proposed studies are that pathological apoptosis of lymphocytes and dysregulated production of IFN-a are integral to the pathogenesis of EVHF. The studies in this application will examine these hypotheses at multiple levels, ranging from the molecular to in vivo in the rhesus macaque model of EVHF . [unreadable] [unreadable]